Editors' ChoiceCELL DEATH

p53: Jack of all (cell death) trades, master of all

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Science Translational Medicine  31 Jan 2018:
Vol. 10, Issue 426, eaar7526
DOI: 10.1126/scitranslmed.aar7526

Abstract

p53 has well-established roles in modulating many forms of cell death including apoptosis, autophagy, necrosis, necroptosis, and increasingly, ferroptosis as well.

Ferroptosis is a form of nonapoptotic, iron-dependent cell death that results from the accumulation of toxic lipid reactive oxygen species (ROS). Physiologically, ferroptosis has been identified as a contributor to cell loss following ischemia-reperfusion injury in the kidney as well as the brain, but its regulation is not yet fully understood. Typically, the cystine/glutamate antiporter system xc- actively suppresses ferroptosis by importing a substrate (cysteine) needed to synthesize the antioxidant glutathione. Inhibiting transporter function using the small molecule erastin2 thus triggers ferroptosis. Mutant forms of the tumor suppressor p53 have been identified as regulators of ferroptosis, but whether the wild-type p53 protein promotes or suppresses this process has been unclear.

To address this lack of clarity, a group led by one of the discoverers of ferroptosis has explored the role of p53 in cysteine deprivation–induced ferroptosis. In contrast to some previous findings, Tarangelo et al. report that p53 activation delays the induction of ferroptosis in several well-defined models and allows cells to avoid ferroptosis induced by metabolic stress long enough for potential rescue by cysteine replacement and continued clonogenic survival. This was reported based on the use of several cell line models and CRISPR/Cas9-mediated gene editing, which provides evidence that p53 stabilization may actually suppress ferroptosis instead of promoting it. Importantly, the mechanism by which p53 suppresses ferroptosis was found to be a p21-mediated retardation of glutathione depletion, thus reducing the build-up of ROS. Although this was not completely universal (noncancerous IMR-90 fetal lung fibroblasts did not exhibit this same p53-mediated protection), it does support the idea that p53 expression could suppress ferroptosis in certain contexts, which may be of importance for understanding and reducing ischemia-reperfusion injuries in vital tissues. In addition, expression of wild-type p53 in cancer cells may enable them to better survive metabolic stress, which may be relevant to ongoing research aimed at targeting cancer metabolism as a potential therapy.

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